What We Might Learn from Mighty Mice

Two recent articles featuring Charles River scientists illustrate how advances in molecular genetics and tumor biology are finally opening doors for humanized mice in cancer.

As we all know, the pendulum in cancer treatment has shifted toward antibody drug conjugates, checkpoint inhibitors, cancer vaccines and modifying T cells (chimeric antigen receptor (CAR)-modified cells), which rely on the immune system in different ways to fight the disease.

It’s not surprising, then, that the models are also trying to act more human, and they are getting better and better at it. Humanized mouse models are just that. Human tissue and cells are engrafted and function as human ones. The earliest humanized mouse models were only able to produce human immune cells for a short duration, but the human immune responses sustained by later humanized mouse models have gotten much stronger. Different gene editing tools, such as CRISPR/Cas9 or TALENs, are also helping us refine the models to make them work better.

One remarkable advance is the marriage of humanized mice with patient-derived tumor xenograft (PDX) models—mice implanted with cancerous tissue from human patients—that is bringing us closer and closer to a clinically relevant model in oncology research.

The magazine Contract Pharma featured a full-length article recently by Charles River scientist Julia Schueler that discussed how humanized PDX models are enabling us to measure immune responses induced by drug compounds against human tumors growing in a human tumor environment. These refinements are helping us to find new drug targets that either modulate the tumor microenvironment in order to support more effective tumor cell killing or evoke an anti-tumor immune response.

“The field of preclinical oncology is evolving tremendously and is rapidly moving towards innovative therapeutic strategies translating into tangible benefit for cancer patients,” Schueler told Eureka. “The advent of novel therapies has triggered a need for advanced preclinical models to investigate their efficacy and mode of action. PDX-based model platforms are able to make a significant input to the drug development pipeline as they mirror very closely the clinical situation.”

The magazine GEN also covered humanized mice recently, pointing out that the development of gene editing tools like CRISPR and TALENS are getting us past some of the early roadblocks that prevented us from producing mouse models with human immune systems and human tumors.

Vincent Vuaroqueaux, who heads the biomarker development and bioinformatics department at CRL in Freiburg, told GEN that their collection of over 450 PDX models use assay platforms that allow them to “evaluate compound efficacy and selectivity in a heterogeneous cellular context and to identify the most sensitive tumor subtypes.”

If one thinks about humanized mouse models the way we do the electric car, one could say that we’ve finally moved beyond the earliest prototypes, where the ideas looked good conceptually but didn’t translate well to highway driving. But humanized mice are still a ways from being considered a mainstream member of the mouse model family. These cancer articles suggest we are getting closer, at least.